Cystic fibrosis (CF) is an autosomal recessive lethal disease that mainly affects the Caucasian populations. Chronic lung infections with Pseudomonas aeruginosa is the leading cause of the morbidity and mortality in CF. Although CFTR mutations predispose the host with increased susceptibility to this and other bacterial pathogens, it is still unclear what innate susceptibility mechanisms are required for the establishment of initial phase of bacterial lung colonizations. To better understand the etiology of bacterial lung infections in conjunction with genetic defects in CF, we identified a P. aeruginosa-susceptible mouse strain and will use this inbred mice to map and identify a mouse susceptibility gene. Using a bacterial aerosol infection mouse model, we screened seven inbred mice for the altered susceptibility to P. aeruginosa and S. aureus lung colonizations. DBA/2 mice were extremely susceptible to lung colonizations by both CF-relevant pathogens while C57BL/6, C3H/HeN, and NJ mice displayed a resistant phenotype. This susceptibility trait is autosomal recessive and seems to be controlled by a single allele. While DBA/2 neutrophils were bactericidal, the delay of neutrophil infiltrations to the lungs in response to bacterial aerosol challenges appeared to be associated with increased susceptibility. In this proposal, we will further examine the genetic basis of bacterial lung infections in mice by pursuing the following two specific aims: 1) to map a mouse susceptibility locus to P. aeruginosa and S. aureus lung infections; and 2) to identify the components of innate lung defenses associated with the P. aeruginosa and S. aureus clearance. We also plan to produce a congenic CFTR mutant mouse in DBA/2 background to test whether homozygous CFTR mice carrying P. aeruginosa-susceptible allele will naturally acquire lung infections as seen in humans with CF. The discovery of the mouse susceptibility gene may lead to the identification of the human homologue (lung-specific modifier gene) presumed to mediate susceptibility in the initial phase of infection. [unreadable] [unreadable]